Neisseria meningitidis is a commensal organism that is found frequently in the throat of healthy adolescents (Maiden, M. C. et al. (2008) J Infect Dis.; Mueller, J. E. et al. (2007) Emerg Infect Dis 13:847-854; Trotter, C. L. et al. (2006) Epidemiol Infect 134:556-566; Bogaert, D. et al. (2005) Clin Infect Dis 40:899-902; Verdu, M. E. et al. (2001) Epidemiol Infect 127:245-259; Ala'Aldeen, D. A. et al. (2000) J Clin Microbiol 38:2311-2316). Rarely the organism invades the bloodstream and causes meningitis or rapidly fatal sepsis.
As far as is known, the organism is strictly a human pathogen. Reliable animal models of meningococcal disease have been difficult to develop (Lewis, T. et al. (1943) J Clin Invest 22:375-385; Ashton, F. E. et al. (1989) Microb Pathog 6:455-458; Zarantonelli, M. L. et al. (2007) Infect Immun 75:5609-5614). Many encapsulated strains of N. meningitidis that are highly pathogenic in humans are readily cleared from the bloodstream of commonly used experimental animals such as rabbits (Lewis, T. et al. (1943) J Clin Invest 22:375-385), mice (Zarantonelli, M. L. et al. (2007) Infect Immun 75:5609-5614; Oftung, F. et al. (1999) FEMS Immunol Med Microbiol 26:75-82; Holbein, B. E. et al. (1979) Infect Immun 24:545-551), or rats (variably, see, below). In addition, meningococcal strains have been reported to vary in their abilities to cause bacteremia in infant rats (see, e.g., Welsch, J. A. et al. (2004) J Immunol 172:5606-5615, Hou, V. C. et al. (2005) J Infect Dis 192:580-590; Toropainen, M. et al. (2005) Vaccine 23:4821-4833; Toropainen, M. et al. (2005) Infect Immun 73:4694-4703; Toropainen, M. et al. (2001) Microb Pathog 30:139-148; Toropainen, M. et al. (2006) Infect Immun 74:2803-2808).
N. meningitidis binds human complement factor H (fH) (Schneider, M. C., et al. (2006) J Immunol 176:7566-7575; Madico, G. et al. (2006) J Immunol 177:501-510), a molecule that down-regulates complement activation. Binding of human fH increases resistance of the organism to complement-mediated bacterial killing and may be an important mechanism that enables N. meningitidis to circumvent innate host defenses. With N. gonorrhoeae, binding of fH is restricted to human fH, which may in part explain species-specific restriction of natural gonococcal infection (Ngampasutadol, J. et al. (2008) J Immunol 180:3426-3435). The importance of serum fH on susceptibility of humans to meningococcal disease has been underscored by recent epidemiological observations that a single nucleotide polymorphism (C-496T) within a presumed NF-κB-responsive element in the promoter region of the cfH gene was associated with higher serum fH levels (C/C homozygous genotype) and an increased risk of acquiring meningococcal disease (Haralambous, E. et al. (2006) Scand J Infect Dis 38:764-771).
Considerable data indicate that serum complement-mediated bactericidal antibody confers protection against meningococcal disease (Goldschneider, I. et al. (1969) J Exp Med 129:1307-1326; I. et al. (1969) J Exp Med 129:1327-1348; Borrow, R. et al. (2005) Vaccine 23:2222-2227; Balmer, P. et al. (2004) Expert Rev Vaccines 3:77-87; Andrews, N et al. (2003) Clin Diagn Lab Immunol 10:780-786; Borrow, R. et al. (2001) Infect Immun 69:1568-1573). The minimum protective serum titer is estimated to be between 1:4 and 1:8 when measured with human complement. Assessment of bactericidal antibody titers has become a gold standard for assessing whether a human subject has mounted a protective immune response against Neisseria. 
However, human complement is difficult to obtain (due in no small part to the fact that most human sera have naturally-acquired antibodies to N. meningitidis, which makes them unsuitable for serving as a source of human complement). Large numbers of healthy donors must be screened and their sera shown to lack antibody to provide suitable complement for use in the assays. Therefore, several standardized protocols for group A and C bactericidal assays use infant rabbit serum as a complement source instead of human serum (Maslanka, S. E. et al. (1997) Clin Diagn Lab Immunol 4:156-167; Jodar, L. et al. (2000) Biologicals 28:193-197). Assays using rabbit serum as a complement source have been widely used to infer vaccine effectiveness and as a basis of licensure of new meningococcal vaccines. Although rabbit complement was selected for these protocols because of greater ease of standardization, it has been known for many years that rabbit complement augments serum bactericidal titers as compared with titers measured with human complement (Zollinger, W. D. et al. (1983) Infect Immun 40:257-264; Santos, G. F. et al. (2001) Clin Diagn Lab Immunol 8:616-623). While serum bactericidal titers measured with rabbit complement have been correlated with the effectiveness of meningococcal vaccination introduced to large populations (Borrow, R. et al. (2005) Vaccine 23:2222-2227; Balmer, P. et al. (2004) Expert Rev Vaccines 3:77-87; N et al. (2003) Clin Diagn Lab Immunol 10:780-786), many of these sera would lack bactericidal activity if tested with human complement.
Thus, the correlations observed with rabbit complement may not accurately or totally reflect the actual mechanisms by which the vaccine-induced antibodies conferred protection. For example, the positive titers measured with rabbit complement could be a surrogate for alternative mechanisms of clearing N. meningitidis when human complement is present and antibody concentrations or quality are insufficient to elicit bactericidal activity but are sufficient to support opsonophagocytosis (Welsch, J. A. et al. (2007) Clin Vaccine Immunol 14:1596-1602; Plested, J. S. et al. (2008) Clin Vaccine Immunol 15:799-804).